It is established that renal medulla possesses antihypertensive function that is likely accomplished by the coordinated action of multiple autocrine and paracrine factors, including prostaglandins, nitric oxide, endothelins, etc. Renal medullary prostaglandins, like many other natriuretic factors, are capable of increasing their synthesis rate in response to excess salt and promote sodium and water excretion. In consistent with this notion, we found that COX-2 expression in renal medulla is remarkably stimulated by chronic salt loading and intramedullary infusion of COX-2 blocker NS-398 significantly reduces urine flow rate. These observations strongly indicate involvement of renal medullary COX-2 in sodium balance and blood pressure control. Large numbers of clinical trials have shown that edema is among the most common site effects of COX-2 inhibition. Experimental data from animal studies indicate that systemic administration of COX-2 blockers reduces urinary sodium excretion and increases blood pressure, and these effects are likely due to inhibition of COX-2 in renal medulla. We hypothesize that under changing states of fluid balance, renal medullary COX-2 undergoes dynamic changes in its expression in order to adjust urinary sodium excretion to stabilize blood pressure and that COX-2 interacts with other natriuretic factors such as nitric oxide and endothelins to coordinate their natriuretic actions. To test the hypotheses, we propose the following Specific Aims: 1) investigate the role and mechanism of high salt-induced renal medullary COX-2 expression in sodium balance and blood pressure regulation; 2) investigate the interaction of renal medullary COX-2 and nitric oxide system in sodium balance and blood pressure regulation; and 3) investigate the interaction of renal medullary COX-2 and endothelin-B receptor in sodium balance in blood pressure regulation. These studies are expected to establish the antihypertensive function of renal medullary COX-2 and to define the interrelationship among various depressor/natriuretic factors. The information resulted from these studies will provide new insight into the molecular mechanism responsible for long-term control of arterial blood pressure.